Our studies will focus on defining the role that kidney-derived Apolipoprotein M (ApoM) plays in lipid accumulation and proximal tubule cell death during Acute Kidney Injury (AKI). ApoM in the serum is mainly present in High Density Lipoproteins (HDL), however, ApoM is also expressed in liver and kidney tissue. Our preliminary studies show that kidney-derived ApoM is mainly expressed in the proximal tubule, and that its expression is reduced during AKI. We find also increased shedding of urinary ApoM that precedes changes in blood urea nitrogen and serum creatinine in wild type mice as well as human ApoM transgenic mice exposed to cisplatin. Since recent studies support the role of ApoM as an anti-inflammatory and anti-atherogenic lipoprotein, we plan to use wild type mice, human ApoM transgenic mice and ApoM knockout mice (available to us from the laboratory of Dr Lars Bo Nielsen, University of Copenhagen) to compare the effects of cisplatin and ischemia reperfusion injury on renal function . We will determine the effect(s) of increased expression of kidney ApoM on the influx of inflammatory cells that occurs during ischemia reperfusion and cisplatin-mediated AKI. In addition, we will determine in human ApoM transgenic mice, whether increased accumulation of kidney neutral lipids mediated by reduced expression of ApoM in the proximal tubule leads to proximal tubule cell death and ARF. We expect to see amelioration of kidney function in human ApoM transgenic mice when compared to wild type mice. Finally, we will use primary cultures obtained from human ApoM transgenic mice, or TKPTS cells (immortalized proximal tubule cell line) infected with adeno ApoM, to determine 1) the mechanisms by which increased expression of ApoM is cytoprotective, and whether the cytoprotective response of increased ApoM relates to reduced accumulation of neutral lipids, reduced apoptotic/necrotic cell death, when these proximal tubules are exposed to either cisplatin or hypoxia/ reoxygenation injury. Our preliminary studies also show that the use of PPARalpha ligand like fibrates prevent cisplatin-induced urinary shedding of kidney-derived ApoM and ameliorate kidney function. We plan to examine whether the expression, secretion and function of ApoM in proximal tubular cells in culture are different in proximal tubules isolated from PPARalpha transgenic mice when compared to proximal tubules isolated from wild type mice. Overall, our studies will contribute to a better understanding of the metabolic effects of kidney-derived apolipoprotein M, will define its role as an early biomarker of AKI, and will elucidate the protective mechanisms of increasing PPARalpha function and activity in the proximal tubule.

Public Health Relevance

Potential Impact to Veterans Health Care: Acute kidney injury is a serious complication seen not only in combat but also in our hospitalized veteran patients, resulting in increased morbidity, mortality, and length of hospital stay. Our proposed studies will examine the role of apolipoprotein M as potential contributor to the observed accumulation of neutral lipids in kidney tissue during AKI. The use of PPARalpha ligand like fibrates offers a novel therapeutic tool to reduce kidney tissue damage, and to reduce the high morbidity and mortality associated with the development of AKI